rs1057520004
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000546.6(TP53):c.647T>G(p.Val216Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 35
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.V216G pathogenic mutation (also known as c.647T>G), located in coding exon 5 of the TP53 gene, results from a T to G substitution at nucleotide position 647. The valine at codon 216 is replaced by glycine, an amino acid with dissimilar properties. Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Two other variants at the same codon, p.V216M (c.646G>A) and p.V216L (c.646G>T), have been detected in patients with features of Li-Fraumeni syndrome and demonstrated loss of function in mulitiple studies (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Bougeard G et al. J. Clin. Oncol. 2015 Jul;33:2345-52; Zerdoumi Y et al. Hum Mol Genet, 2017 07;26:2812). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -
Li-Fraumeni syndrome Uncertain:1
This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with glycine at codon 216 of the TP53 protein (p.Val216Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. This variant has not been reported in the literature in individuals with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 376671). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the Val216 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26014290, 24549055, 25669829, 12826609, 17724467, 21232794). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. An experimental study in yeast has shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at